Browsing by Subject "Adipose tissue"

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  • Hetemäki, Natalia; Mikkola, Tomi S.; Tikkanen, Matti J.; Wang, Feng; Hämäläinen, Esa; Turpeinen, Ursula; Haanpää, Mikko; Vihma, Veera; Savolainen-Peltonen, Hanna (2021)
    Objective: Although the ovaries produce the majority of estrogens in women before menopause, estrogen is also synthesized in peripheral tissues such as adipose tissue (AT). The typical female AT distribution, concentrated in subcutaneous and femoro-gluteal regions, is estrogen-mediated, but the significance of estrogen synthesis in AT of premenopausal women is poorly understood. Design and Methods: Serum and subcutaneous and visceral AT homogenates from 28 premenopausal women undergoing non-malignant surgery were analyzed for estrone, estradiol, and serum estrone sulfate (E1S) concentrations with liquid chromatography-tandem mass spectrometry. Isotopic precursors were used to measure enzyme activities of estrone-producing steroid sulfatase and estradiol-producing 17?-hydroxysteroid dehydrogenases (17?-HSD). Messenger RNA (mRNA) expression levels of genes for estrogen-metabolizing enzymes were analyzed using real-time reverse transcription quantitative polymerase chain reaction. Results: While estradiol was the predominant circulating active estrogen, estrone dominated in AT, with a higher concentration in visceral than subcutaneous AT (median, 2657 vs 1459 pmol/kg; P = 0.002). Both AT depots converted circulating E1S to estrone, and estrone to estradiol. Median levels of estrone were five to ten times higher in subcutaneous and visceral AT than in serum (P <0.001) and the estradiol level in visceral AT was 1.3 times higher than in serum (P <0.005). The local estrone concentration in visceral AT correlated positively with mRNA expression of estrone-producing enzyme aromatase (r = 0.65, P = 0.003). Waist circumference correlated positively with increased estradiol production in subcutaneous AT (r = 0.60, P = 0.039). Conclusions: Premenopausal AT demonstrated high estrogenic enzyme activity and considerable local estrogen concentrations. This may be a factor promoting female-typical AT distribution in premenopausal women.
  • Jokinen, Riikka; Pirnes-Karhu, Sini; Pietilainen, Kirsi H.; Pirinen, Eija (2017)
    Obesity, a chronic state of energy overload, is characterized by adipose tissue dysfunction that is considered to be the major driver for obesity associated metabolic complications. The reasons for adipose tissue dysfunction are incompletely understood, but one potential contributing factor is adipose tissue mitochondrial dysfunction. Derangements of adipose tissue mitochondrial biogenesis and pathways associate with obesity and metabolic diseases. Mitochondria are central organelles in energy metabolism through their role in energy derivation through catabolic oxidative reactions. The mitochondrial processes are dependent on the proper NAD(+)/NADH redox balance and NAD+ is essential for reactions catalyzed by the key regulators of mitochondrial metabolism, sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs). Notably, obesity is associated with disturbed adipose tissue NAD(+) homeostasis and the balance of SIRT and PARP activities. In this review we aim to summarize existing literature on the maintenance of intracellular NAD(+) pools and the function of SIRTs and PARPs in adipose tissue during normal and obese conditions, with the purpose of comprehending their potential role in mitochondrial derangements and obesity associated metabolic complications. Understanding the molecular mechanisms that are the root cause of the adipose tissue mitochondrial derangements is crucial for developing new effective strategies to reverse obesity associated metabolic complications.
  • Kochumon, Shihab; Arefanian, Hossein; Sindhu, Sardar; Shenouda, Steve; Thomas, Reeby; Al-Mulla, Fahd; Tuomilehto, Jaakko; Ahmad, Rasheed (2021)
    Steroid receptor RNA activator 1 (SRA1) is involved in pathophysiological responses of adipose tissue (AT) in obesity. In vitro and animal studies have elucidated its role in meta-inflammation. Since SRA1 AT expression in obesity/type 2 diabetes (T2D) and the relationship with immune-metabolic signatures remains unclear, we assessed AT SRA1 expression and its association with immune–metabolic markers in individuals with obesity/T2D. For this, 55 non-diabetic and 53 T2D individuals classified as normal weight (NW; lean), overweight, and obese were recruited and fasting blood and subcutaneous fat biopsy samples were collected. Plasma metabolic markers were assessed using commercial kits and AT expression of SRA1 and selected immune markers using RT-qPCR. SRA1 expression was significantly higher in non-diabetic obese compared with NW individuals. SRA1 expression associated with BMI, PBF, serum insulin, and HOMA-IR in the total study population and people without diabetes. SRA1 associated with waist circumference in people without diabetes and NW participants, whereas it associated inversely with HbA1c in overweight participants. In most study subgroups AT SRA1 expression associated directly with CXCL9, CXCL10, CXCL11, TNF-α, TGF-β, IL2RA, and IL18, but inversely with CCL19 and CCR2. TGF-β/IL18 independently predicted the SRA1 expression in people without diabetes and in the total study population, while TNF-α/IL-2RA predicted SRA1 only in people with diabetes. TNF-α also predicted SRA1 in both NW and obese people regardless of the diabetes status. In conclusion, AT SRA1 expression is elevated in people with obesity which associates with typical immunometabolic markers of obesity/T2D, implying that SRA1 may have potential as a biomarker of metabolic derangements.
  • Karaman, Sinem; Hollmen, Maija; Robciuc, Marius R.; Alitalo, Annamari; Nurmi, Harri; Morf, Bettina; Buschle, Dorina; Alkan, H. Furkan; Ochsenbein, Alexandra M.; Alitalo, Kari; Wolfrum, Christian; Detmar, Michael (2015)
    Objective: Elevated serum levels of the lymphangiogenic factors VEGF-C and -D have been observed in obese individuals but their relevance for the metabolic syndrome has remained unknown. Methods: K14-VEGFR-3-Ig (sR3) mice that constitutively express soluble-VEGFR-3eIg in the skin, scavenging VEGF-C and -D, and wildtype (WT) mice were fed either chow or high-fat diet for 20 weeks. To assess the effect of VEGFR-3 blockage on adipose tissue growth and insulin sensitivity, we evaluated weight gain, adipocyte size and hepatic lipid accumulation. These results were complemented with insulin tolerance tests, FACS analysis of adipose tissue macrophages, in vitro 3T3-L1 differentiation assays and in vivo blocking antibody treatment experiments. Results: We show here that sR3 mice are protected from obesity-induced insulin resistance and hepatic lipid accumulation. This protection is associated with enhanced subcutaneous adipose tissue hyperplasia and an increased number of alternatively-activated (M2) macrophages in adipose tissue. We also show that VEGF-C and -D are chemotactic for murine macrophages and that this effect is mediated by VEGFR-3, which is upregulated on M1 polarized macrophages. Systemic antibody blockage of VEGFR-3 in db/db mice reduces adipose tissue macrophage infiltration and hepatic lipid accumulation, and improves insulin sensitivity. Conclusions: These results reveal an unanticipated role of the lymphangiogenic factors VEGF-C and -D in the mediation of metabolic syndrome-associated adipose tissue inflammation. Blockage of these lymphangiogenic factors might constitute a new therapeutic strategy for the prevention of obesity-associated insulin resistance. (C) 2014 The Authors. Published by Elsevier GmbH.
  • Lundbom, Jesper; Bierwagen, Alessandra; Bodis, Kalman; Szendroedi, Julia; Kaprio, Jaakko; Rissanen, Aila; Lundbom, Nina; Roden, Michael; Pietilainen, Kirsi H. (2016)
    Background. Obese twins have lower saturated and higher long-chain polyunsaturated fatty acids (FA) in subcutaneous adipose tissue (SAT) compared to their lean monozygotic (MZ) co-twin. Whether this holds for metabolically distinct deep (DSAT) and superficial (SSAT) depots is unknown. Here we use non-invasive magnetic resonance spectroscopy (MRS) to measure the FA unsaturation in body mass index (BMI) discordant MZ twins in DSAT and SSAT and their relationship to ectopic fat content and body fat distribution. The main finding is further confirmed in an independent cohort using standardized measurement times. Methods. MRS and magnetic resonance imaging were used to measure DSAT and SSAT unsaturation and their relationship to intramyocellular lipids (IMCL), hepatocellular lipids (HCL) and the amount of subcutaneous (SAT) and visceral adipose tissue (VAT) in 16 pairs of healthy monozygotic twins (MZ) discordant for BMI. A second independent cohort of 12 healthy volunteers was used to measure DSAT unsaturation and IMCL with standardized measurement time. One volunteer also underwent repeated random measurements of DSAT unsaturation and IMCL. Results. In accordance with biopsy studies SSAT unsaturation was higher in the heavier twins (15.2 +/- 1.0% vs. 14.4 +/- 1.5%, P = 0.024) and associated with SAT volume (R = 0.672, P = 0.001). DSAT unsaturation did not differ between twins (11.4 +/- 0.8 vs. 11.0 +/- 1.0, P = 0.267) and associated inversely with IMCL content (R = -0.462, P = 0.001). The inverse association between DSAT unsaturation and IMCL was also present in the participants of the second cohort (R = -0.641, P = 0.025) and for the repeated sampling at random of one person (R = -0.765, P = 0.027). Conclusions. DSAT and SSAT FA unsaturation shows distinct associations with obesity and IMCL in MZ twins, reflecting compartment-specific metabolic activities. The FA unsaturation in the DSAT depot associates inversely with IMCL content, which raises the possibility of cross talk between the DSAT depot and the rapid turnover IMCL depot. (C) 2016 Elsevier Inc. All rights reserved.
  • Savolainen-Peltonen, Hanna; Vihma, Veera; Wang, Feng; Turpeinen, Ursula; Hämäläinen, Esa; Haanpää, Mikko; Leidenius, Marjut; Tikkanen, Matti J.; Mikkola, Tomi S. (2018)
    Circulating estrogens fluctuate during the menstrual cycle but it is not known whether this fluctuation is related to local hormone levels in adipose tissue. We analyzed estrogen concentrations and gene expression of estrogen-regulating enzymes in breast subcutaneous adipose tissue in premenopausal women with (n = 11) and without (n = 17) estrogen receptor-positive breast cancer. Estrone (E-1) was the predominant estrogen in premenopausal breast adipose tissue, and E-1 and mRNA expression of CYP19A1 in adipose tissue correlated positively with BMI. Adipose tissue estradiol (E-2) concentrations fluctuated during the menstrual cycle, similarly to the serum concentrations. In women with breast cancer median adipose tissue E-1 (1519 vs. 3244, p <.05) and E-2 (404 vs. 889 pmol/kg, p <.05) levels were lower in the follicular than in the luteal phase whereas in control women no significant differences were observed. In the follicular phase, mRNA expressions of HSD17B1 (median 0.06; interquartile range 0.05-0.07 vs. 0.17; 0.03-0.2, p = .010) and CYP19A1 (0.08; 0.07-0.14 vs. 0.22; 0.09-0.54, p = .025) were lower in women with breast cancer than in controls. In conclusion, the changes in adipose tissue E-1 and E-2 concentrations and the estrogen-regulating CYP19A1 and HSD17B1 during the menstrual cycle may be related to dysfunctional local estrogen metabolism in women with breast cancer.
  • Vihma, Veera; Heinonen, Sini; Naukkarinen, Jussi; Kaprio, Jaakko; Rissanen, Aila; Turpeinen, Ursula; Hämäläinen, Esa; Hakkarainen, Antti; Lundbom, Jesper; Lundbom, Nina; Mikkola, Tomi S.; Tikkanen, Matti J.; Pietiläinen, Kirsi H. (2018)
    Objective: Obesity may alter serum steroid concentrations and metabolism. We investigated this in healthy young women with increased body fat and their leaner co-twin sisters. Design: Age and genetic background both strongly influence serum steroid levels and body composition. This is a cross-sectional study of 13 female monozygotic twin pairs (age, 23-36 years), ten of which were discordant for body mass index (median difference in body weight between the co-twins, 19 kg). Methods: We determined body composition by dual energy X-ray absorptiometry and magnetic resonance imaging, serum androgens by liquid chromatography-tandem mass spectrometry, and mRNA expression of genes in subcutaneous adipose tissue and adipocytes. Results: The heavier women had lower serum dehydroepiandrosterone (DHEA), dihydrotestosterone (DHT), and sex hormone-binding globulin (SHBG) (P <0.05 for all) compared to their leaner co-twins with no differences in serum testosterone or androstenedione levels. Serum DHEA correlated inversely with %body fat (r = -0.905, P = 0.002), and DHT positively with SHBG (r = 0.842, P = 0.002). In adipose tissue or adipocytes, expressions of STS (steroid sulfatase) and androgen-related genes were significantly higher in the heavier compared to the leaner co-twin, and within pairs, correlated positively with adiposity but were not related to serum androgen levels. None of the serum androgen or SHBG levels correlated with indices of insulin resistance. Conclusions: Serum DHEA levels were best predicted by %body fat, and serum DHT by SHBG. These or other serum androgen concentrations did not reflect differences in androgen-related genes in adipose tissue. General or intra-abdominal adiposity were not associated with increased androgenicity in young women.
  • Vihma, Veera; Naukkarinen, Jussi; Turpeinen, Ursula; Hämäläinen, Esa; Kaprio, Jaakko; Rissanen, Aila; Heinonen, Sini; Hakkarainen, Antti; Lundbom, Jesper; Lundbom, Nina; Mikkola, Tomi S.; Tikkanen, Matti J.; Pietiläinen, Kirsi H. (2017)
    Obesity and ageing are associated with lower serum testosterone levels in men. How fat distribution or adipose tissue metabolism, independent of genetic factors and age, are related to sex steroid metabolism is less clear. We studied the associations between adiposity and serum sex hormone concentrations, and mRNA expression of genes regulating sex hormone metabolism in adipose tissue in young adult male monozygotic (MZ) twin pairs. The subjects [n = 18 pairs; mean age, 32 years; individual body mass indexes (BMIs) 22-36 kg/m(2)] included 9 male MZ twin pairs discordant for BMI [infra-pair difference (Delta) in BMI >= 3 kg/m(2)]. Sex steroid concentrations were determined by liquid chromatography-tandem mass spectrometry, body composition by dual-energy X-ray absorptiometry and magnetic resonance imaging, and mRNA expressions from subcutaneous adipose tissue by Affymetrix. In BMI-discordant pairs (mean Delta BMI = 5.9 kg/m2), serum dihydrotestosterone (DHT) was lower [mean 1.9 (SD 0.7) vs. 2.4 (1.0) nmol/l, P = 0.040] and mRNA expressions of DHT-inactivating AKR1C2 (P = 0.021) and cortisol-producing HSD11B1 (P = 0.008) higher in the heavier compared to the leaner co-twins. Serum free 17 beta-estradiol (E2) was higher [2.3 (0.5) vs. 1.9 (0.5) pmol/l, P = 0.028], and in all twin pairs, serum E2 and estrone concentrations were higher in the heavier than in the leaner co-twins [107 (28) vs. 90 (22) pmol/l, P = 0.006; and 123 (43) vs. 105 (27) pmol/l, P = 0.025]. Within all twin pairs, i.e. independent of genetic effects and age, 1) the amount of subcutaneous fat inversely correlated with serum total and free testosterone, DHT, and sex hormone-binding globulin (SHBG) concentrations (P <0.01 for all), 2) infra-abdominal fat with total testosterone and SHBG (P <0.05), and 3) liver fat with SHBG (P = 0.006). Also, 4) general and intra-abdominal adiposity correlated positively with mRNA expressions of AKR1C2, HSD11B1, and aromatase in adipose tissue (P <0.05). In conclusion, acquired adiposity was associated with decreased serum DHT and increased estrogen concentrations, independent of genetic factors and age. The reduction of DHT could be linked to its increased degradation (by AKR1C2 and HSD11B1) and increased estrogen levels to increased adiposity-related expression of aromatase in adipose tissue.
  • Lallukka, Susanna; Luukkonen, Panu K.; Zhou, You; Isokuortti, Elina; Leivonen, Marja; Juuti, Anne; Hakkarainen, Antti; Orho-Melander, Marju; Lundbom, Nina; Olkkonen, Vesa M.; Lassila, Riitta; Yki-Järvinen, Hannele (2017)
    Increased liver fat may be caused by insulin resistance and adipose tissue inflammation or by the common I148M variant in PNPLA3 at rs738409, which lacks both of these features. We hypothesised that obesity/insulin resistance rather than liver fat increases circulating coagulation factor activities. We measured plasma prothrombin time (PT, Owren method), activated partial thromboplastin time (APTT), activities of several coagulation factors, VWF:RCo and fibrinogen, and D-dimer concentration in 92 subjects divided into groups based on insulin sensitivity [insulin-resistant ('IR') versus insulin-sensitive ('IS')] and PNPLA3 genotype (PNPLA3(148MM/MI) vs PNPLA3(148II)). Liver fat content (H-1-MRS) was similarly increased in 'IR' (13 +/- 1%) and PNPLA3(148MM/MI) (12 +/- 2%) as compared to 'IS' (6 +/- 1%, p
  • Vihma, Veera; Wang, Feng; Savolainen-Peltonen, Hanna; Turpeinen, Ursula; Hamalainen, Esa; Leidenius, Marjut; Mikkola, Tomi S.; Tikkanen, Matti J. (2016)
    Estrone is the most abundant estrogen after the menopause. We developed a liquid chromatography-tandem mass spectrometric method (LC-MS/MS) for determination of estrone in adipose tissue. Subcutaneous adipose tissue from the breast was collected during elective surgery in postmenopausal women undergoing mastectomy for treatment of breast cancer (n = 13) or reduction mammoplasty (controls, n = 11). Homogenized adipose tissue was extracted with organic solvents and the estrone fraction was purified by LH-20 column chromatography from the excess of lipids. The concentration of estrone was analyzed by LC-MS/MS. The method was accurate with an intra-assay variation of 8% and an interassay variation of 10%. The median concentration of estrone in subcutaneous adipose tissue from the breast did not differ between breast cancer and control women, 920 pmol/kg and 890 pmol/kg, respectively. In breast cancer patients but not in the controls, breast adipose tissue estrone levels correlated positively with the serum estrone concentration. In conclusion, the new method provides a reliable means to measure estrone concentrations in adipose tissue in postmenopausal women. (C) 2015 Elsevier Ltd. All rights reserved.
  • Tsai, Pei-Chien; Glastonbury, Craig A.; Eliot, Melissa N.; Bollepalli, Sailalitha; Yet, Idil; Castillo-Fernandez, Juan E.; Carnero-Montoro, Elena; Hardiman, Thomas; Martin, Tiphaine C.; Vickers, Alice; Mangino, Massimo; Ward, Kirsten; Pietilaeinen, Kirsi H.; Deloukas, Panos; Spector, Tim D.; Vinuela, Ana; Loucks, Eric B.; Ollikainen, Miina; Kelsey, Karl T.; Small, Kerrin S.; Bell, Jordana T. (2018)
    Background: Tobacco smoking is a risk factor for multiple diseases, including cardiovascular disease and diabetes. Many smoking-associated signals have been detected in the blood methylome, but the extent to which these changes are widespread to metabolically relevant tissues, and impact gene expression or metabolic health, remains unclear. Methods: We investigated smoking-associated DNA methylation and gene expression variation in adipose tissue biopsies from 542 healthy female twins. Replication, tissue specificity, and longitudinal stability of the smoking-associated effects were explored in additional adipose, blood, skin, and lung samples. We characterized the impact of adipose tissue smoking methylation and expression signals on metabolic disease risk phenotypes, including visceral fat. Results: We identified 42 smoking-methylation and 42 smoking-expression signals, where five genes (AHRR, CYP1A1, CYP1B1, CYTL1, F2RL3) were both hypo-methylated and upregulated in current smokers. CYP1A1 gene expression achieved 95% prediction performance of current smoking status. We validated and replicated a proportion of the signals in additional primary tissue samples, identifying tissue-shared effects. Smoking leaves systemic imprints on DNA methylation after smoking cessation, with stronger but shorter-lived effects on gene expression. Metabolic disease risk traits such as visceral fat and android-to-gynoid ratio showed association with methylation at smoking markers with functional impacts on expression, such as CYP1A1, and at tissue-shared smoking signals, such as NOTCH1. At smoking-signals, BHLHE40 and AHRR DNA methylation and gene expression levels in current smokers were predictive of future gain in visceral fat upon smoking cessation. Conclusions: Our results provide the first comprehensive characterization of coordinated DNA methylation arid gene expression markers of smoking in adipose tissue. The findings relate to human metabolic health and give insights into understanding the widespread health consequence of smoking outside of the lung.
  • Tsai, Pei-Chien; Glastonbury, Craig A; Eliot, Melissa N; Bollepalli, Sailalitha; Yet, Idil; Castillo-Fernandez, Juan E; Carnero-Montoro, Elena; Hardiman, Thomas; Martin, Tiphaine C; Vickers, Alice; Mangino, Massimo; Ward, Kirsten; Pietiläinen, Kirsi H; Deloukas, Panos; Spector, Tim D; Viñuela, Ana; Loucks, Eric B; Ollikainen, Miina; Kelsey, Karl T; Small, Kerrin S; Bell, Jordana T (BioMed Central, 2018)
    Abstract Background Tobacco smoking is a risk factor for multiple diseases, including cardiovascular disease and diabetes. Many smoking-associated signals have been detected in the blood methylome, but the extent to which these changes are widespread to metabolically relevant tissues, and impact gene expression or metabolic health, remains unclear. Methods We investigated smoking-associated DNA methylation and gene expression variation in adipose tissue biopsies from 542 healthy female twins. Replication, tissue specificity, and longitudinal stability of the smoking-associated effects were explored in additional adipose, blood, skin, and lung samples. We characterized the impact of adipose tissue smoking methylation and expression signals on metabolic disease risk phenotypes, including visceral fat. Results We identified 42 smoking-methylation and 42 smoking-expression signals, where five genes (AHRR, CYP1A1, CYP1B1, CYTL1, F2RL3) were both hypo-methylated and upregulated in current smokers. CYP1A1 gene expression achieved 95% prediction performance of current smoking status. We validated and replicated a proportion of the signals in additional primary tissue samples, identifying tissue-shared effects. Smoking leaves systemic imprints on DNA methylation after smoking cessation, with stronger but shorter-lived effects on gene expression. Metabolic disease risk traits such as visceral fat and android-to-gynoid ratio showed association with methylation at smoking markers with functional impacts on expression, such as CYP1A1, and at tissue-shared smoking signals, such as NOTCH1. At smoking-signals, BHLHE40 and AHRR DNA methylation and gene expression levels in current smokers were predictive of future gain in visceral fat upon smoking cessation. Conclusions Our results provide the first comprehensive characterization of coordinated DNA methylation and gene expression markers of smoking in adipose tissue. The findings relate to human metabolic health and give insights into understanding the widespread health consequence of smoking outside of the lung.
  • Hyvärinen, Kati; Tuomainen, Anita M.; Laitinen, Saara; Alfthan, Georg; Salminen, Irma; Leinonen, Maija; Saikku, Pekka; Kovanen, Petri T.; Jauhiainen, Matti; Pussinen, Pirkko J. (2013)